HLH-2004 for untreated hemophagocytic lymphohistiocytosis (HLH)

Regimen in use at

Regimen

Study	Evidence
Henter et al. 2007 (HLH-2004)	Non-randomized

Immunosuppressive therapy

• Start allogeneic stem cell transplant (SCT) donor search
• Dexamethasone (Decadron) in a tapering schedule as follows:
  • Weeks 1 & 2: 10 mg/m² (route not specified) once per day
  • Weeks 3 & 4: 5 mg/m² (route not specified) once per day
  • Weeks 5 & 6: 2.5 mg/m² (route not specified) once per day
  • Week 7: 1.25 mg/m² (route not specified) once per day
  • Week 8: "taper then discontinue"
• Etoposide (Vepesid) as follows:
  • Weeks 1 & 2: 150 mg/m² IV twice per week
  • Weeks 3 to 8: 150 mg/m² IV once per week
• Cyclosporine A 3 mg/kg/dose by mouth twice per day (total dose per day is 6 mg/kg), if normal kidney function. **Titrate doses with goal of levels around 200 mcg/L (monoclonal, trough level). It was not clear from the paper whether this is modified or non-modified cyclosporine.

Intrathecal therapy

To "start only if progressive neurological symptoms or if an abnormal CSF has not improved," maximum of 4 doses, as follows:

• • Weeks 3 to 6: Methotrexate (MTX) (dosed by age as listed below) IT once per week, as follows:
    • less than 1 year old: 6 mg each dose
    • 1 to 2 years old: 8 mg each dose
    • 2 to 3 years old: 10 mg each dose
    • Greater than 3 years old: 12 mg each dose
  • Weeks 3 to 6: Prednisolone IT once per week, as follows:
    • less than 1 year old: 4 mg each dose
    • 1 to 2 years old: 6 mg each dose
    • 2 to 3 years old: 8 mg each dose
    • Greater than 3 years old: 10 mg each dose

Supportive medications

• Prophylactic cotrimoxazole (5 mg/kg of trimethoprim equivalent), three times weekly, start on week 1 and treat onwards
• An oral antimycotic from weeks 1 to 9
• IvIG 0.5 g/kg IV once every 4 weeks
• "Gastroprotection suggested" for weeks 1 to 9

8-week course; patients with resolved, non-familial, non-genetically verified disease stopped therapy. Patients with familial, genetically verified, persistent, or reactivation/relapsed disease continued to continuation therapy, until an allogeneic HCT could be performed, as follows:

Continuation therapy

Starts during week 9.

• Dexamethasone (Decadron) 10 mg/m² (route not specified) once per day for three days, every two weeks (on even weeks)
• Etoposide (Vepesid) 150 mg/m² IV once every two weeks (on odd weeks)
• Cyclosporine A by mouth twice per day, aiming for trough blood levels of 200 mcg/L (not clear from the paper whether this is modified or non-modified)
• Proceed with allogeneic stem cell transplant (SCT) as soon as an acceptable donor is found, such as:
  • HLA-idential record donor
  • Matched unrelated donor
  • Mismatched unrelated donor
  • Family haploidentical donor

Used continuously, with allogeneic stem cell transplant done when possible

References

1. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. link to full article at ResearchGate link to original article contains verified protocol link to study protocol PubMed
   1. Update: Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, Ishii E, Janka G, Ladisch S, Lehmberg K, McClain KL, Minkov M, Montgomery S, Nanduri V, Rosso D, Henter JI. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017 Dec 21;130(25):2728-2738. Epub 2017 Sep 21. link to original article PubMed